This application addresses broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and the specific Challenge Topic, 01-CA-103: The Role of Health Behaviors in Cancer Prevention. Chronic psychological stress and the resulting systemic increase in stress neurotransmitters noradrenaline and adrenaline and the glucocorticoid stress hormone cortisol enhance vulnerability to numerous diseases. However, the effects of stress on the prevention of cancer has not been studied to date. We have shown that two of the most common and most deadly cancers, small airway-derived pulmonary adenocarcinoma (PAC) and pancreatic ductal adenocarcinoma (PDAC) are stimulated in vitro and in vivo by cAMP-dependent signaling downstream of beta-adrenergic receptors (b-ARs) and that glucocorticoids stimulate these cells by increasing cAMP signaling. These findings suggest that a stress-related increase in noradrenaline and adrenaline (that are agonists for b-ARs) and cortisol will stimulate the development and progression of these cancers, thus counteracting the effects of cancer preventive agents. The disappointing and as yet poorly understood disconnect between promising results of preclinical testing and failure of these agents in clinical trials may thus be caused by the absence of stress in carefully maintained systems for the testing of anti- cancer drugs in vitro and in laboratory animals. On the other hand, we have shown in PAC and PDAC cells in vitro that the stimulating cAMP signaling downstream of b-ARs is inhibited by the neurotransmitter g- aminobutyric acid (GABA) that inhibits the activation of adenylyl cyclase. In addition, we have shown in mouse xenografts from PDAC and PAC that GABA reverses the cancer promoting effects of nicotine, which include a nicotinic receptor-induced systemic increase in noradrenaline and adrenaline. Based on these data we will test the hypotheses in xenografts of two human PAC and two PDAC cell that the development and progression of PAC and PDAC is stimulated by psychological stress, decreases the responsiveness to cancer prevention by a non-steroidal anti-inflammatory agent, and that treatment with GABA reverses these effects. We will use nude mice subjected to chronic social stress and assess the impact of this condition on cancer prevention by daily measurements of xenograft size as well as the quantitative determination of molecular markers by real-time PCR and Western blotting accompanied by histopathology and immunohistochemistry. Specific Aim 1: To test the hypothesis that psychological stress stimulates the development and progression of PDAC and PAC. Specific Aim 2: To test the hypothesis that psychological stress reduces the cancer preventive effects of the COX-2 inhibitor celecoxib on PDAC and PAC xenografts. Specific Aim 3: To test the hypothesis that treatment with GABA reverses the effects of psychological stress in mice without celecoxib prevention. Specific Aim 4: To test the hypothesis that GABA reverses the adverse effects of psychological stress on cancer prevention with celecoxib. Data generated by this 2-year project have a high chance to significantly improve the effectiveness of PAC and PDAC prevention and also provide a foundation for improved prevention of cancer of the colon, prostate, breast, stomach and ovary, all of which are stimulated by beta-adrenergic signaling. This application addresses broad Challenge Area (01) Behavior, Behavioral Change, and Prevention and the specific Challenge Topic, 01-CA-103: The Role of Health Behaviors in Cancer Prevention. Chronic psychological stress and the resulting systemic increase in stress neurotransmitters noradrenaline and adrenaline and the glucocorticoid stress hormone cortisol enhance vulnerability to numerous diseases. Low socioeconomic status, which creates chronic psychological stress and is particularly prevalent in African Americans, is associated with a significantly higher incidence and mortality of all cancers. However, the negative modulation of cancer prevention by psychological stress has not been studied to date and no information exists as to how such negative effects can be overcome. The current project will test the hypotheses in mice with xenografts of cell lines from human lung adenocarcinomas and pancreatic ductal adenocarcinomas that the development and progression of these cancers is stimulated by psychological stress, decreases the responsiveness to cancer prevention by a non steroidal anti-inflammatory agent, and that treatment with gamma-aminobutyric acid (GABA) reverses these effects. Data generated by this 2-year project will rapidly improve the prevention of lung cancer and panreatic cancer and lay the foundation for the rapid development of more successful prevention and therapy of cancer of the colon, prostate, breast, stomach and ovary.